Towards Translation of MU-CN29: New Therapeutic Nanoparticle for Drug-Resistant NSCLC

MU-CN29 的转化：治疗耐药 NSCLC 的新型治疗纳米颗粒

基本信息

批准号：
10529911
负责人：
Raghuraman Kannan
金额：
$ 62.21万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-17 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10529911
关键词：
Animal Cancer Model Animal Model Antibodies Automobile Driving Biodistribution Biological Assay Bypass Cancer Etiology Cancer Model Cancer Patient Canis familiaris Cell Death Cells Clinical Clinical Trials Data Disease remission Dose Down-Regulation Drug Kinetics Drug Targeting Drug resistance Epidermal Growth Factor Receptor Future Gelatin Goals Guidelines Hepatic Human Immune Immune checkpoint inhibitor Immune response Immunocompetent Immunotherapy In Vitro Kidney Lead Malignant neoplasm of lung Metastatic Neoplasm to the Lung Mind Molecular Mus Mutate Mutation NF-kappa B Nanoconjugate Non-Small-Cell Lung Carcinoma Oncogenes Outcome Pathway interactions Patients Pharmaceutical Preparations Phenotype Production Proteins Protocols documentation Publishing Quality Control RNA Degradation Radiology Specialty Resistance Safety Signal Pathway Signal Transduction Small Interfering RNA Survival Rate System Therapeutic Therapeutic Agents Toxic effect Toxicology Translations Treatment Efficacy Tyrosine Kinase Inhibitor Woman Xenograft procedure analytical method axl receptor tyrosine kinase base cancer therapy canine model checkpoint therapy clinical efficacy clinical translation clinically relevant combat immune resistance immunoregulation improved in vivo in vivo Model inhibitor inhibitor therapy knock-down lung cancer cell men mortality mouse model mutant nanoparticle nanoparticle drug novel novel strategies novel therapeutics overexpression protein expression response sarcoma stem survival outcome synergism therapeutic target therapeutically effective tumor tumor growth tumor microenvironment

项目摘要

ABSTRACT Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality in both men and women. Despite rapid therapeutic advances, the 5-year survival rate of EGFR-mutant NSCLC remains a dismal 16% for the past several decades. In particular, the rapid emergence of resistance to widely used treatments, such as the tyrosine kinase inhibitor (TKI), is the key obstacle to achieving long-term NSCLC patient survival. Further, patients with EGFR mutated tumors fail to respond to immune checkpoint inhibitors (ICIs), leaving them with little to no hope of a long-term remission. Therefore, identifying the molecular determinants of resistance and developing a therapeutic that targets the chemo- and immune-resistant pathways, is the best chance to improve survival rates in NSCLC patients with an EGFR mutation. We hypothesize that MU-CN29, the lead targeted siRNA nanoconjugate, restores sensitivity to tyrosine kinase inhibitors in resistant NSCLC. We further postulate that MU-CN29 will induce a systemic immune response, priming the tumor microenvironment for immunotherapy via ICIs. Therefore, the central objective of this TTNCI proposal is to develop, evaluate, and validate MU-CN29 as an effective therapeutic agent for resistant NSCLC. Our promising in vitro and in vivo experimental results confirmed the crosstalk between the resistance-driving receptor tyrosine kinase AXL and FN14 pathways in drug resistant NSCLC. Additionally, we found that the co-knockdown of both AXL and FN14, using MU-CN29, covalently attached with the dual siRNAs, sensitized the resistant tumors to tyrosine kinase inhibitor (TKI), in vitro and in vivo. To enable translation of MU-CN29 to human trials, in this proposal, we will manufacture the nanoparticles as per FDA guidelines, perform detailed toxicology studies in murine and canine subjects, and evaluate the therapeutic efficacy in clinically relevant animal models. The specific aims of this applications are: (1) Determine MU-CN29 clinical-grade production protocols; (2) Determine the safety and efficacy of MU-CN29 in murine NSCLC models; (3) Establish safety of MU-CN29 in canine cancer patients. The data will validate MU-CN29 nanoparticle platform as a promising strategy to combat drug resistance in NSCLC and catalyze clinical trials in the future.

抽象的非小细胞肺癌（NSCLC）是男性和女性癌症死亡的主要原因。尽管尽管治疗进展迅速，但 EGFR 突变 NSCLC 的 5 年生存率仍然只有 16%，令人沮丧。过去几十年。特别是，对广泛使用的治疗方法的耐药性迅速出现，例如酪氨酸激酶抑制剂（TKI）是非小细胞肺癌患者实现长期生存的关键障碍。更远， EGFR 突变肿瘤患者对免疫检查点抑制剂 (ICIs) 没有反应，导致他们长期缓解的希望很小甚至没有。因此，确定耐药性的分子决定因素和开发一种针对化疗和免疫耐药途径的治疗方法是最好的机会提高携带 EGFR 突变的 NSCLC 患者的生存率。我们假设 MU-CN29，先导靶向 siRNA 纳米缀合物可恢复耐药 NSCLC 中对酪氨酸激酶抑制剂的敏感性。我们进一步假设 MU-CN29 将诱导全身免疫反应，启动肿瘤微环境通过 ICI 进行免疫治疗。因此，本 TTNCI 提案的中心目标是开发、评估和验证 MU-CN29 作为耐药 NSCLC 的有效治疗剂。我们在体外和体内的前景广阔实验结果证实了耐药驱动受体酪氨酸激酶 AXL 和耐药 NSCLC 中的 FN14 通路。此外，我们发现 AXL 和 FN14 的共同击倒，使用与双 siRNA 共价连接的 MU-CN29 使耐药肿瘤对酪氨酸激酶敏感抑制剂（TKI），体外和体内。为了将 MU-CN29 转化为人体试验，在本提案中，我们将根据 FDA 指南制造纳米颗粒，对小鼠和犬类进行详细的毒理学研究受试者，并评估临床相关动物模型的治疗效果。本次活动的具体目标应用有：（1）确定MU-CN29临床级生产方案； (2)确定安全性和 MU-CN29 在小鼠 NSCLC 模型中的功效； (3) 确定MU-CN29在犬癌症患者中的安全性。这些数据将验证 MU-CN29 纳米颗粒平台是对抗耐药性的有前途的策略 NSCLC并催化未来的临床试验。